Transition-state docking of flunitrazepam and progesterone in cytochrome P450
Rydberg, Patrik LU ; Hansen, Sine Myrup ; Kongsted, Jacob LU ; Norrby, Per-Ola ; Olsen, Lars and Ryde, Ulf LU
(2008)
In Journal of Chemical Theory and Computation
4(4).
p.673-681
- Abstract
- We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly... (More)
- We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs. better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1207454
- author
- Rydberg, Patrik
LU
; Hansen, Sine Myrup
; Kongsted, Jacob
LU
; Norrby, Per-Ola
; Olsen, Lars
and Ryde, Ulf
LU
- organization
- publishing date
- 2008
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Chemical Theory and Computation
- volume
- 4
- issue
- 4
- pages
- 673 - 681
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000254710700014
- scopus:58149107172
- ISSN
- 1549-9618
- DOI
- 10.1021/ct700313j
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
- id
- ad74f420-622b-4f87-8e9b-f0f351561fd0 (old id 1207454)
- date added to LUP
- 2016-04-01 12:03:44
- date last changed
- 2023-02-07 02:35:21
@article{ad74f420-622b-4f87-8e9b-f0f351561fd0,
abstract = {{We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs. better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software.}},
author = {{Rydberg, Patrik and Hansen, Sine Myrup and Kongsted, Jacob and Norrby, Per-Ola and Olsen, Lars and Ryde, Ulf}},
issn = {{1549-9618}},
language = {{eng}},
number = {{4}},
pages = {{673--681}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of Chemical Theory and Computation}},
title = {{Transition-state docking of flunitrazepam and progesterone in cytochrome P450}},
url = {{https://lup.lub.lu.se/search/files/136745962/107_ts_docking_final.pdf}},
doi = {{10.1021/ct700313j}},
volume = {{4}},
year = {{2008}},
}